Hyperhidrosis is a condition characterized by abnormally increased sweating or perspiration, in excess of that required for regulation of body temperature. Hyperhidrosis is associated with a significant quality of life burden from a psychological, emotional, and social perspective. As such, it has been referred to as a “silent handicap.” Hyperhidrosis is a medical condition in which a person sweats excessively and unpredictably. People with hyperhidrosis may sweat even when the temperature is cool or when they are at rest. Estimates provide that at least 3% of the global population suffers from hyperhidrosis (also known as excessive sweating, excessive perspiration, or diaphoresis), namely at least about 211 million people.
Hyperhidrosis can either be generalized or localized to specific pails of the body. Hands, feet, armpits, and the groin area are among the most active regions of perspiration due to the relatively high concentration of sweat glands. When excessive sweating is localized (e.g., palms, soles, face, underarms, scalp) it is referred to as primary or focal hyperhidrosis. Generalized or secondary hyperhidrosis usually involves the body as a whole and is the result of an underlying condition.
Hyperhidrosis can also be classified depending by onset, either congenital or acquired. Focal hyperhidrosis is found to start during adolescence or even before and seems to be inherited as an autosomal dominant genetic trait. Primary or focal hyperhidrosis must be distinguished from secondary hyperhidrosis, which can start at any point in life. The latter form may be due to a disorder of the thyroid or pituitary glands, diabetes mellitus, tumors, gout, menopause, certain drugs, or mercury poisoning.
Hyperhidrosis may also be divided into palmoplantar (symptomatic sweating of primarily the hands or feet), gustatory, generalized and focal hyperhidrosis.
Alternatively, hyperhidrosis may be classified according to the amount of skin affected and its possible causes. In this approach, excessive sweating in an area greater an 100 cm2 (16 sq in) (up to generalized sweating of the entire body) is differentiated from sweating that affects only a small area.
Primary focal hyperhidrosis refers to excessive sweating that is not caused by another medical condition, nor is it a side effect of medications. The excessive sweating is the medical condition. This type of sweating occurs on very specific areas of the body (described as focal areas) and may be relatively “symmetric,” in that both the left and light sides of the body are affected similarly. As noted above, the most common focal areas are the hands, feet, underarms, and head or face. Primary focal hyperhidrosis often begins in childhood or adolescence, especially hyperhidrosis of the hands and feet. Interestingly, although people with primary focal hyperhidrosis have episodes of excessive sweating at least once a week, they usually do not experience excessive sweating white sleeping. Primary focal hyperhidrosis may be inherited and many members of the same family may suffer from this condition.
Symptoms associated with primary focal hyperhidrosis include one or more, and in particular two or more of: (i) sweat is bilateral and relatively symmetrical, meaning a subject sweats the same amount on both sides of the body; (ii) excess sweat impairs daily activities; (iii) at least one episode a weak, (iv) onset of excess sweat is earlier than age 25; (v) a positive family history, namely other members of the subject's family suffer from similar sweating problems; and (vi) the is no excess sweating when asleep. Some dermatologists believe upwards of 90 percent of people who present with excessive sweating will be diagnosed with primary hyperhidrosis.
The other main type of hyperhidrosis is referred to as secondary generalized hyperhidrosis. This type of excessive sweating is caused by another medical condition or is a side affect of a medication. Unlike with primary focal hyperhidrosis, people with secondary hyperhidrosis experience sweating on larger or other areas of the body, described as generalized areas. Another key difference between the two types of hyperhidrosis is that people with secondary generalized hyperhidrosis may often experience their sweating symptoms while sleeping. With secondary hyperhidrosis, excessive sweating usually starts in adulthood, whereas primary hyperhidrosis starts in childhood or adolescence. Finding a potential treatment for secondary excessive sweating often involves first determining what, if any, underlying medical condition or medication may be the root of the problem. Conditions that cause second hyperhidrosis include: Acromegaly, Anxiety conditions, Cancer, Carcinoid syndrome, Certain medications and substances of abuse, Glucose control disorders, Heart disease, Hyperthyroidism: Lung disease; Menopause; Parkinson disease; Pheochromocytoma; Spinal cord injury; Stroke; and Tuberculosis or other infections.
The primary symptom of hyperhidrosis is wetness. Visible signs of sweating may be noted during a doctor's visit. Tests may also be used to diagnose excessive sweating, including: (i) Starch-iodine test: an iodine solution is applied to the sweaty area; after it dries, starch is sprinkled on the area; the starch-iodine combination turns a dark blue color wherever there is excess sweat; and (ii) Paper test: special paper is placed on the affected area to absorb the sweat, and then weighed; the heavier, the more sweat has accumulated.
Current treatments may include:
Antiperspirants: Excessive-sweating may be controlled with strong anti-perspirants, which plug the sweat ducts. Products containing 10% to 20% aluminum chloride hexahydrate are the first line of treatment for underarm sweating. Some patients may be prescribed a product containing a higher dose of aluminum chloride, which is applied nightly onto the affected areas. Antiperspirants can cause skin irritation, and large doses of aluminum chloride can damage clothing.
Iontophoresis: This procedure uses electricity to temporarily turn off the sweat gland. It is most effective for sweating of the hands and feet. The hands or feet are placed into water, and then a gentle current of electricity is passed through it. The electrically is gradually increased until the patient feels a light tingling sensation. The therapy lasts about 10 to 20 minutes and requires several sessions. Side effects include skin cracking and blisters, although rare.
Botox: Botulinum toxin type A (Botox) is used to treat severe underarm sweating. Botulinum toxin is injected into the underarm to temporarily block the nerves that stimulate sweating. Side effects include injection-site pain and flu-like symptoms. Botox used for sweating of the palms can cause mild, out temporary weakness and intense pain.
Endoscopic thoracic sympathectomy (ETS): In severe cases, a minimally-invasive surgical procedure called sympathectomy may be recommended when other treatments do not work. The procedure turns off the signal that tells the body to sweat excessively. It is usually done on patients whose palms sweat much more heavily than normal it may also be used to treat extreme sweating of the face. ETS does not work as well for those with excessive armpit sweating.
Surgery: This is surgery to remove the sweat glands in the armpits. Methods used include laser, curettage (scraping), excision (cutting), or liposuction. These procedures are done using local anesthesia.
Alternative options, including oral medications, are needed with different safety, metabolic, tolerability, and efficacy profiles to effectively treat hyperhidrosis.
Mecamylamine (N2,3,3-tetramethylbicyclo[2.2.1] heptan-2-amine hydrochloride), was developed and characterized by Merck & Co., Inc., as a ganglionic blocker with clinically significant hypotensive actions (Stone et al., Chemistry and structure-activity relationships of mecamylamine and derivatives, J. Med. Pharm. Chem., 5(4):665-690. 1962). Mecamylamine was sold under the tradename Inversine®. Depending on preferred naming convention, the chemical name for mecamylamine may also be N,2,3,3-tetramethylnorbornan-2-amine. Mecamylamine exists as a racemic mixture of enantiomers and can be obtained according to the methods and processes described in U.S. Pat. No. 5,986,142, incorporated herein by reference for its teaching regarding methods of producing mecamylamine.
Unique characteristics of mecamylamine, including oral efficacy for treating hypertension, rapid onset, long duration of action, and nearly complete absorption from the gastrointestinal tract, made the drug a more desirable alternative to the then-existing ganglionic blockers. The average total daily dose of Inversine® (mecamylamine hydrochloride) used to treat high blood pressure was 25 mg, usually administered in three divided doses. The safety/tolerability profile of mecamylamine in humans has been established during decades of clinical use as an antihypertensive agent. The most common adverse reactions to the marketed drug include constipation, orthostatic dizziness, urinary retention, and blurred vision.
U.S. Pat. No. 7,101,916, herein incorporated by reference, provides for a pharmaceutical composition that includes a therapeutically effective amount of exo-S-mecamylamine or a pharmaceutical acceptable salt thereof, substantially free of exo-R-mecamylamine, in combination with a pharmaceutically acceptable carrier, wherein the pharmaceutical composition is characterized by a higher overall therapeutic index than a substantially similar pharmaceutical composition comprising, exo-R-mecamylamine substantially free of exo-S-mecamylamine. The medical conditions disclosed therein include but are not limited to substance addiction (involving nicotine, cocaine, alcohol, amphetamine, opiate, other psychostimulant and a combination thereof), aiding smoking cessation, treating weight gain associated with smoking cessation, hypertension, hypertensive crisis, herpes type I and II, Tourette's Syndrome and other tremors, cancer (such as small cell lung cancer), atherogenic profile, neuropsychiatric disorders (such as bipolar disorder, depression, anxiety disorder, panic disorder, schizophrenia, seizure disorders, Parkinson's disease and attention deficit hyperactivity disorder), chronic fatigue syndrome, Crohn's disease, autonomic dysreflexia, and spasmogenic intestinal disorders. Hyperhidrosis is not described or disclosed in U.S. Pat. No. 7,101,916. The patent discloses that exo-S-mecamylamine may be administered intravenously, intramuscularly, transdermally, intrathecally, orally or by bolus injection. The dosage of exo-S-mecamylamine for treating the identified diseases is described in a range of about 0.5 mg to about 1000 mg, depending on dosage form, and exo-mecamylamine may be administered one to four times per day. Examples include a dose of about 2.5 mg per day for adults with drug-resistant Tourette's Syndrome and 1 mg per day or less for a small child with mild ADHD.
Purified exo-S-mecamylamine and exo-R-mecamylamine can be obtained according to methods discussed in U.S. Pat. No. 7,101,916, and references cited therein, also incorporated herein by reference for their teaching regarding the production of purified mecamylamine enantiomers. Exo-S-mecamylamine may also be referred to as dexmecamylamine, S-mecamylamine, TC-5214, or (S)—N,2,3,3-tetramethylnorboran-2-amine, and includes a pharmaceutically acceptable salt thereof.
Dexmecamylamine is a use-dependent potent inhibitor of the α3 nicotinic receptor subtype (e.g., α3β2 and α3β4). Such receptors are expressed in the urothelium and regulate bladder smooth muscle contraction. (Beckel et al., Expression of functional nicotinic acetylcholine receptors in rat urinary bladder epithelial cells, Am. J. Physiol. Renal Physiol. 290; F103-110, 2006). A clinical study was performed to evaluate the safety, tolerability, and efficacy of dexmecamylamine (TC-5214) for the treatment of Overactive Bladder (OAB). The study included a three- or five-week screening period, followed by a 12-week treatment period during which patients received either one of three doses of dexmecamylamine or placebo twice dally, randomized in a ratio of 2:1:1:1 (placebo, low dose, mid dose, high dose), with a two-week follow-up period. A total of 768 subjects with overactive bladder were randomized into the double-blind treatment period of the study. On Jul. 28, 2014, Targacept announced top-line results from the Phase 2b clinical trial of TC-5214 as a treatment for overactive bladder (OAB). In the trial, the high dose of TC-5214 demonstrated mixed results on the co-primary endpoints by providing a statistically significant reduction in micturition frequency (p=0.033) and an improvement that did not reach statistical significance on episodes of urinary incontinence (p=0.379) per 24 hours, after 12 weeks of treatment. As a consequence of these results, Targacept discontinued further development of TC-5214 in OAB. In this trial, TC-5214 was considered generally safe and well tolerated. There was a placebo-corrected 15.1% rate of constipation and a 5.9% rate of urinary tract infection in the high dose group. See also, PCT Application No. PCT/US2013/030640, which published as WO 2013/142162 A1.
Dexmecamylamine, however, has not been studied previously in a model or study related to hyperhidrosis.
There remains a need for effective treatment of hyperhidrosis, with specific focus toward symptomatic relief, having an improved side effect and tolerability profile.